Department of Medicinal Chemistry and Pharmacognosy, University of Illinois, Chicago, Illinois 60612.
Department of Pharmaceutical Sciences, Linus Pauling Science Center, Oregon State University, Corvallis, Oregon 97331.
Toxicol Sci. 2018 Oct 1;165(2):389-395. doi: 10.1093/toxsci/kfy147.
Patients exposed to long acting anticoagulant rodenticides (LAARs) are typically administered large amounts of oral vitamin K1 (VK1) to counteract life-threatening anticoagulant effects. Although VK1 treatment effectively prevents mortality, additional methods are needed to reduce the long duration of VK1 treatment which can last for months at high expense. We developed a model of brodifacoum (BDF) poisoning, one of the most potent LAARs, in adult male New Zealand White (NZW) rabbits. The LD50 for oral BDF was determined to be 192 μg/kg, similar to that calculated for adult rats. However, in contrast to rats, NZW rabbits exhibited severe internal hemorrhage including in the brain, symptoms which mimic what occurs in cases of human poisoning. Similar to warfarin, BDF and other LAARs undergo enterohepatic recirculation which contributes to their long half-lives. We therefore tested effects of cholestyramine (CSA), an FDA-approved bile sequestrant, on BDF-induced mortality. When given daily (0.67 g/kg, oral) starting the day of BDF administration, CSA reduced mortality from 67% to 11%. At the same CSA prevented the increase in clotting time, and reduced the decrease in core body temperature due to BDF. Given its excellent safety record and that it is approved for children older than 6 years, these findings suggest CSA could be considered as an adjunct to VK1 for treatment of LAAR poisoning.
接触长效抗凝血灭鼠剂（LAARs）的患者通常需要大量口服维生素 K1（VK1）来对抗危及生命的抗凝作用。虽然 VK1 治疗可以有效地预防死亡，但还需要其他方法来减少 VK1 治疗的长时间，因为 VK1 治疗可能需要数月且费用高昂。我们在成年雄性新西兰白兔（NZW）中建立了溴鼠灵（BDF）中毒模型，BDF 是最有效的 LAAR 之一。口服 BDF 的 LD50 确定为 192 μg/kg，与成年大鼠的计算值相似。然而，与大鼠不同的是，NZW 兔子表现出严重的内出血，包括大脑内出血，这些症状类似于人类中毒的情况。与华法林类似，BDF 和其他 LAARs 经历肠肝再循环，这导致它们的半衰期长。因此，我们测试了考来烯胺（CSA），一种美国 FDA 批准的胆汁螯合剂，对 BDF 诱导的死亡率的影响。当从 BDF 给药的当天开始每天给予（0.67 g/kg，口服）时，CSA 将死亡率从 67%降低到 11%。在相同的 CSA 下，可以预防 BDF 引起的凝血时间延长，并减少核心体温下降。鉴于其良好的安全性记录，并且已批准用于 6 岁以上的儿童，这些发现表明 CSA 可以考虑作为 VK1 的辅助剂用于治疗 LAAR 中毒。
